The present invention relates to a preparation for external use containing a basic drug whose long-lasting action has been improved.
Dermal preparations for external use are excellent dosage forms permitting drugs to act directly on the sites of action and they find wide use.
As a general characteristic of preparations for external use, low absorption through the skin can be pointed out. Thus far, therefore, studies have been made of techniques for promoting drug absorption through the skin with the use of percutaneous absorption promoters. However, preparations for external use which use such percutaneous absorption promoters currently fail to obtain persistent effects.
As a method for allowing a drug to stay at the affected site to improve its long-lasting action, Japanese Patent Kokai Hei No. 10-265409 discloses a technique which involves adding fatty acid esters of aliphatic polyhydric alcohols, and certain types of polyhydric alcohols.
With regard to injections, on the other hand, WO95/35093 discloses a method for sustained release of a drug administered by injection and this technique comprises adding a polyacid and a water soluble nonionic polymer to the drug and gelling the mixture in a physiological environment to permit persistent drug release.
These techniques hitherto known in the field of techniques for prolonging the action of preparations for external use have been unsuccessful in showing a sufficiently long-lasting action on the skin damaged by wounds or inflammations, or at mucosal sites.
The present invention aims to provide a new technique which can achieve a long-lasting action of a drug even on a damaged skin or at a mucosal site.
The inventors of the present invention have conducted various studies to solve the problem. As a result, they found that when polyvinyl pyrrolidone and carboxyvinyl polymer were simultaneously used with a basic drug, and the mixture was adjusted to a specific pH, the mixture gave an excellent preparation for external use capable of showing a long-lasting action even when applied to a damaged skin or a mucosal site. This finding led them to accomplish the present invention.
That is, the present invention is a preparation for external use which contains a basic drug, polyvinyl pyrrolidone and carboxyvinyl polymer and which has a pH of 4 to 9.
The basic drug herein refers to a compound having a basic moiety in the structure, preferably, a compound having an amino group. Its examples include anti-inflammatories (bufexamac, indometacin, diclofenac, antipyrine, mefenamic acid, piroxicam, oxyphenbutazone, phenylbutazone, mepirizole, etc.), hair growers (minoxidil, etc.), vasoconstrictors (naphazoline, phenylephrine, etc.), antimycotics (croconazole, miconazole, econazole, clotrimazole, isoconazole, pyrrolnitrin, terbinafine, omoconazole, lanoconazole, liranaftate, itraconazole, fluconazole, tolnaftate, sulconazole, bifonazole, etc.), and local anesthetics (lidocaine, dibucaine, oxybuprocaine, etc.). Their salts are also usable.
The amount of the basic drug added differs according to its type of the drug, but is generally 0.1 to 5% by mass based on the entire mass of the preparation.
As the carboxyvinyl polymer used herein, those which are generally used as a base ingredient and the like in pharmaceuticals can be used. The use of a base ingredient such as hyaluronic acid instead of carboxyvinyl polymer does not offer a sufficient long-lasting action. Thus, carboxyvinyl polymer is an essential ingredient for exhibiting a long-lasting action in the preparation for external use. The amount of the carboxyvinyl polymer added is preferably 0.1 to 6 parts by mass per part by mass of the basic drug.
As the polyvinyl pyrrolidone used herein, those which are generally used as a base ingredient and the like in pharmaceuticals can be used. The amount of the polyvinyl pyrrolidone added is preferably 0.5 to 10 parts by mass per part by mass of the basic drug.
The preparation for external use according to the present invention may further contain polyethylene glycol and this is preferred because the long-lasting action of the drug on the affected site is further improved. The amount of the polyethylene glycol is preferably 10 to 50% by mass based on the entire mass of the preparation.
The preparation for external use according to the present invention needs to be in the pH range of 4 to 9, but a range of pH 4 to 8 is further preferred. A pH of less than 4 is not preferred in maintaining salability. A pH in excess of 9 may cause skin irritation.
For pH adjustment, use of a neutralizing agent which can be added into the preparation for external use, and an amine-based neutralizing agent is particularly preferred. Preferred examples of the neutralizing agent are triethanolamine, diethanolamine, triethylamine, diethylamine, isopropanolamine, diisopropanolamine, triisopropanolamine, di(2-ethylhexyl)amine, tetrahydroxypropylethylenediamine, and monoethanolamine.
Further addition of alcohols is preferred in terms of adhesion to the skin. No addition of alcohols may result in poor wetting of the skin with a liquid preparation, or poor adhesion of the liquid preparation to the skin, eventually leading to an insufficient pharmacological effect. As the alcohols to be added, common alcohols which can be used in preparations for external use are usable. Preferably, they include, for example, ethanol, isopropanol, propylene glycol, and 1,3-butylene glycol, and these alcohols can be used as mixtures. The amount of the alcohols added is preferably 10 to 70% by mass based on the entire mass of the preparation.
The concept of the preparation for external use as used herein includes preparations for cutaneous administration (liquids, creams, ointments, gels, patches, aerosols, etc.) and transmucosal preparations (nasal drops, oral preparations, suppositories, etc.), and can be in any of these common dosage forms. The present invention is particularly effective in the case of formulating liquid preparations for external use which have so far been defied the efforts to make them release the drug slowly.
The preparation for external use according to the present invention can contain ingredients which can be mixed into preparations for external use in qualitative and quantitative ranges not impairing the effects of the present invention and it can be produced by an ordinary method.
Hereinafter, the present invention will be described in greater detail by the following Examples and Test Example.